Identification and Preliminary SAR Analysis of Novel Type-I Inhibitors of TIE-2 via Structure-Based Virtual Screening and Biological Evaluation in in vitro Models

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• 作者：Peichen Pan ; Sheng Tian ; Huiyong Sun ; Xiaotian Kong ; Wenfang Zhou ; Dan Li ; Youyong Li ; Tingjun Hou
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2015
• 出版时间：December 28, 2015
• 年：2015
• 卷：55
• 期：12
• 页码：2693-2704
• 全文大小：852K
• ISSN：1549-960X

文摘

Angiopoietin (ANG) ligands and their downstream TIE receptors have been validated as the second vascular signaling system involving vessel remodeling and maturation. Among them, the ANG/TIE-2 signaling pathway is involved in numerous life-threatening diseases and has become an attractive potential therapeutic target. Several large-molecule inhibitors targeting the ANG/TIE-2 axis have recently entered clinical phase for the therapy of various solid tumors, but selective small-molecule inhibitors of TIE-2 are still quite limited. In the present work, structure-based virtual screening was performed to search for type-I inhibitors of TIE-2. Of the only 41 compounds selected by our strategy, 8 molecules with the concentration of 25 μg/mL exhibit over 50% inhibitory rate against TIE-2 in in vitro enzymatic activity assay, and the IC₅₀ values of 2 hits are lower than 1 μM. Further optimization and SAR analysis based on compound TP-S1-30 and 31 were carried out by using substructure searching strategy, leading to the discovery of several sub-100 nM inhibitors. Among them, the most potent compound, TP-S1-68, showed an inhibitory IC₅₀ of 0.149 μM. These novel inhibitors of TIE-2 discovered in this study and the analogs of the active core scaffolds can serve as the starting points for further drug development.